Cordarone. Dosage, Side Effects, Interactions
The class III antiarrhythmic drug amiodarone is used as a second choice drug for ventricular and supraventricular cardiac arrhythmias. The active ingredient has a very long half-life of 20 to 100 days.
Cordarone (Amiodarone) is indicated for symptomatic tachycardic supraventricular cardiac arrhythmias that require treatment, e.g. B.
- AV junctional tachycardias
- supraventricular tachycardia in WPW syndrome or
- paroxysmal atrial fibrillation .
It is suitable for patients who do not respond to treatment with other antiarrhythmics or for whom other antiarrhythmics are not indicated.
Serious, symptomatic, tachycardic ventricular arrhythmia.
However, therapy with β-receptor blockers should not be abandoned in favor of therapy with amiodarone.
Amiodarone is the drug of first choice for resuscitation after ventricular tachycardia or ventricular fibrillation.
How Cordarone (Amiodarone) works
Amiodarone is a class III antiarrhythmic drug. It has a strong inhibitory effect on many cardiac arrhythmias that are associated with impaired cardiac conduction. Amiodarone inhibits voltage-gated potassium channels in myocardial tissue. This inhibits potassium efflux in phase III of the action potential and selectively prolongs the repolarization and refractory period of the action potential. The contractile force of the myocardium is not affected. Amiodarone shows dose-dependent, non-competitive inhibition of α- and β-adrenergic activities. This is expressed in a coronary and vasodilating effect. The oxygen supply to the heart is improved and the heart muscle is relieved.
Drugs contain the active ingredient as amiodarone hydrochloride .
After oral administration, 50% of amiodarone hydrochloride is absorbed from the gastrointestinal tract. Accumulation of the substance at its site of action or saturation of the myocardial tissue is decisive for the therapeutic effectiveness. Depending on the saturation dosage, therapeutic effects can be expected over a period of a few days to two weeks.
After injection, the maximum effect is reached after 15 minutes. This is followed by a redistribution into the tissue and a rapid drop in the plasma level within 4 hours. To saturate the tissue stores, the therapy must be continued intravenously or orally.
Amiodarone has a long half-life that varies greatly between individuals (20 to 100 days). The substance accumulates during saturation, particularly in adipose tissue. The steady state is reached within a period of one to several months. Because of these characteristics, the recommended loading dose should be administered to achieve rapid tissue saturation, which is a prerequisite for therapeutic efficacy.
The main route of elimination is via the liver and bile. Amiodarone is primarily metabolised by CYP-3A4 and also by CYP2C8 . 10% of the substance is excreted renally. Due to the low renal excretion, the usual dose can be administered to patients with renal insufficiency. After discontinuation, amiodarone is excreted for several months.
Amiodarone and its metabolite, desethylamiodarone, are able to inhibit the following enzymes of the cytochrome P450 system in vitro: CYP1A1, CYP1A2 , CYP2C9 , CYP2D6 , CYP-3A4, CYP2A6, CYP2B6 and CYP2C8 . In addition, both substances have the potential to inhibit some transporters (such as P-glycoprotein and organic cation transporter (OCT2)). In vivo data have shown an interaction of amiodarone and CYP3A4, CYP2C9, CYP2D6 and P-gp substrates.
In the limited published data available in pediatric patients, no difference from adults was identified. Studies have not been conducted in children and adolescents.
Dosage of Cordarone (Amiodarone)
Careful cardiological monitoring is required to adjust therapy for ventricular cardiac arrhythmia. It may only be carried out if cardiological emergency equipment is available and a monitor control is possible. The following guide values can be used to determine the dose:
- Saturation dose in adults: 600 mg per day for 8-10 days (200 mg 3 times per day)
- Then reduce the dose to a maintenance dose: generally 200 mg (once a day) for 5 days a week.
- In individual cases a loading dose of up to 1200 mg may be required and for the maintenance dose 200-600 mg per day.
- When treating children, the dose should be adjusted depending on body surface area and body weight. Studies have used 10 to 20 mg/kg/day for 7 to 10 days as a loading dose. The maintenance dose should be the minimum effective dose. It can be between 5 to 10mg/kg/day.
Side effects of Cordarone (Amiodarone)
The use of amiodarone must be monitored urgently by a doctor, as the active substance can have serious side effects such as pulmonary fibrosis or hypothyroidism and can even cause cardiac arrhythmias itself.
Below are the side effects of amiodarone in order of frequency:
- Microdeposits on the front surface of the cornea of the eye (Cornea verticillata) can lead to visual disturbances (blurred vision, color halos around light sources). They are complex lipid deposits usually confined to the region below the pupil. They usually resolve 6 to 12 months after stopping the drug
- Nausea, vomiting, taste changes at the start of treatment (saturation dose) that disappear with dose reduction
- Slight elevations in serum transaminases at the start of therapy (normalization usually occurs with dose reduction or spontaneously)
- Acute hepatitis with greatly increased serum transaminases and/or cholestatic jaundice, including liver failure (in isolated cases fatal outcome)
- Hyper- or hypothyroidism (single fatal cases)
- Extrapyramidal tremor, nightmares, sleep disturbances
- Bradycardia (moderate and dose-dependent)
- As a result of the pulmonary toxicity of amiodarone, atypical pneumonia as an expression of a hypersensitivity reaction (hypersensitivity pneumonitis), alveolar or interstitial pneumonia or fibrosis, pleurisy, bronchiolitis obliterans with pneumonia /BOOP can occur. Single fatal cases have been reported. Non-productive cough and shortness of breath are often the first signs of the aforementioned lung changes
- weight loss, fever and weakness
- muscle weakness
- Serious interactions exist with drugs that induce torsades de pointes or that prolong the QT interval.
- Concomitant treatment with drugs that can trigger torsades de pointes (eg, MAO inhibitors , class I and III antiarrhythmics) is therefore contraindicated.
- Drugs known to prolong the QT interval (eg, vincamine , some antipsychotics [eg , sulpiride ], pentamidine IV, and erythromycin IV) may increase the risk of torsades de pointes. Concomitant use should only occur after careful assessment of the potential risks and benefits for each patient. Patients should be monitored for QT prolongation.
- Administration of fluoroquinolones should be avoided in patients being treated with amiodarone.
- Concomitant treatment with drugs that decrease heart rate or cause stimulus or conduction disorders is not recommended.
- Administration with verapamil- and diltiazem – type calcium channel blockers or β-blockers may result in excessive bradycardia, greater degrees of atrioventricular conduction abnormalities, and an additive cardiodepressant effect.
- Concomitant use of medicinal products capable of inducing hypokalemia is not recommended. For example, laxatives that cause hypokalemia can increase the risk of torsades de pointes. Other laxatives should therefore be used in combination with amiodarone.
- Because of the increased risk of developing hypokalemic-induced cardiac arrhythmias (including torsades de pointes), caution is advised with concomitant treatment with the following drugs: potassium-depleting diuretics (e.g. , hydrochlorothiazide , furosemide ), systemic corticosteroids , tetracosactide , or amphotericin B iv
- Hypokalemia must be avoided (and corrected). In the case of torsades de pointes, no antiarrhythmic drugs should be given.
- In rare cases, atropine-resistant bradycardia, drop in blood pressure, conduction disturbances and reduced cardiac output are possible with general anesthesia. Severe respiratory complications (shock lung, ARDS) have been observed very rarely.
- CYP1A1, CYP-1A2, CYP3A4, CYP2C9, CYP2D6 and P-glycoprotein (P-gp) are inhibited by amiodarone and/or its metabolite, desethylamiodarone. This can increase exposure to the substrates of these enzymes and thus their effect and toxicity. A dose adjustment may be necessary. Interactions may persist for several months after stopping amiodarone (due to amiodarone’s long half-life).
- Amiodarone and cardioactive glycosides show a synergistic effect on the heart. This can lead to disturbances in stimulus formation (excessive bradycardia) and atrioventricular conduction when administered at the same time. With digoxin , an increase in digoxin serum levels (due to reduced digoxin clearance) can occur. These patients should be monitored for symptoms of digitalis overdose (precautionary determination of digoxin plasma levels and possible dose adjustment).
- Concomitant use of dabigatran should be used with caution due to an increased risk of bleeding. Dose adjustment of dabigatran may be required.
- CYP2C9 substrates: Vitamin K antagonists ( warfarin , dicoumarol, phenprocoumon ): Enhancement of the anticoagulant effect and consequently increased risk of bleeding. More frequent INR monitoring should be performed during and after treatment with amiodarone. If necessary, a dose adjustment of the vitamin K antagonists is necessary.
- Phenytoin (symptoms of phenytoin overdose include visual disturbances, tremor, dizziness)
- Antiarrhythmics (e.g. quinidine , procainamide , flecainide ).
- CYP2D6 substrates: flecainide (flecainide dose should be adjusted when co-administered).
- Cytochrome P450 3A4 substrates: cyclosporine , fentanyl , statins , lidocaine , tacrolimus, sildenafil , midazolam , triazolam , ergotamine and dihydroergotamine , colchicine
- CYP3A4 and CYP2C8 inhibitors have the potential to inhibit amiodarone metabolism and increase amiodarone exposure. The use of CYP3A4 inhibitors (such as grapefruit juice or certain drugs) should be avoided during treatment with amiodarone.
Amiodarone must not be used in:
- Hypersensitivity to the active substance
- Sinus bradycardia (less than 55 beats per minute)
- All forms of conduction delay (sinoauricular and nodal conduction delay) including diseased sinus node syndrome, AV block II and III. Grades as well as bi- and trifascicular blocks, provided no pacemaker is used (danger of sinus node arrest)
- thyroid disorders
- pre-existing QT prolongation
- iodine allergies
- History of angioneurotic edema (hereditary or idiopathic, e.g. due to previous amiodarone therapy)
- concomitant treatment with MAO inhibitors
- concomitant treatment with medicinal products that may induce torsades de pointes
- Pregnancy unless clearly necessary.
Amiodarone crosses the placenta and has harmful effects on pregnancy, the fetus and the newborn. Growth failure, premature birth and thyroid dysfunction in the newborn are the most common complications. However, hypothyroidism, bradycardia and prolonged QT intervals have also been reported in some neonates. Occasionally, an enlargement of the thyroid gland or heart murmurs were found. Even if the rate of malformations does not appear to be increased, the possibility of cardiac defects should be considered.
Amiodarone should not be used during pregnancy unless clearly necessary. Because of the long half-life of amiodarone, women who wish to have children should wait at least six months after the end of therapy to avoid exposure of the child in early pregnancy.
A passage into breast milk has been demonstrated for the active substance and for the active metabolite. Breast-feeding is not allowed during treatment with amiodarone.
Even when used as directed, amiodarone can change the ability to react to such an extent that the ability to actively participate in road traffic, to operate machines or to work without a secure footing is impaired. This applies to a greater extent at the start of treatment, when the dose is increased and when the drug is changed, as well as in combination with alcohol.
Treatment with this drug requires regular medical supervision.
Further details on this active ingredient can be found in the relevant product information.
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